DESCRIPTION (Investigator's Abstract): The PI has established a cortical cell culture model of DS. The goal of this proposal is to determine the mechanism of degeneration and to identify potential therapeutic agents. Preliminary studies demonstrate that DS neurons generate markedly elevated levels of peroxides prior to cell death. The degeneration of DS neurons is prevented by free radical scavengers and catalase. To determine whether overexpression of superoxide dismutase in DS neurons is the cause of increased hydrogen peroxide accumulation and neuronal degeneration, the expression of SOD will be reduced to the level in control neurons using SOD antisense oligonucleotides. The mechanism of increased oxidative stress will be further examined by determining the levels of antioxidant enzymes and by using specific enzyme inhibitors to determine the contribution of other free radical-generating enzymes. The consequence of defective trophic factor support in DS neurons will be assessed by determining whether exogenous neurotrophic factors prevent peroxide generation and DS neuronal degeneration. To determine whether altered beta amyloid metabolism in DS cortical cultures predisposes to AD pathology, DS cortical neurons will be examined for the formation of amyloid deposits and tau hyperphosphorylation, and the ability of antioxidants to reverse these pathological changes.